TMC207 is a safe and effective drug for the treatment of multidrug-resistant tuberculosis (TB), the results of a randomised, placebo-controlled trial published in the June 4th edition of the New England Journal of Medicine have shown. Patients who received the drug were significantly more likely to have a negative culture result after eight weeks than patients who received standard second-line TB treatment.
The author of an editorial accompanying the study describes the development of the drug as “an important advance in the chemotherapy of tuberculosis.”
In 2006, there were over 9 million cases of TB diagnosed around the world and 1.7 million deaths because of the infection. Many patients with TB are also infected with HIV, and the infection is the leading cause of death amongst HIV-positive individuals around the world.
Treatment for TB consists of therapy with multiple drugs for at least six months. Multidrug-resistant strains of the infection (MDR-TB) have emerged that are resistant to the key first-line anti-TB drugs isoniazid and rifampicin. Furthermore, some strains of the infection, known as extensively drug-resistant TB (XDR-TB) have evolved with resistance to second-line drugs as well.
TMC207 is an investigational drug that belongs to a class of agents known as diarylquinolines. Test tube studies demonstrated that it had considerable activity against drug-resistant TB.
Investigators designed a Phase II, placebo-controlled trial involving patients with newly diagnosed, sputum smear-positive MDR-TB to assess TMC207’s safety, side-effects, pharmacokinetics, and antibacterial action.
The study involved 47 hospitalised patients aged between 18 and 65 years in South Africa. All the patients received a five-drug combination for the treatment of MDR-TB.
They were randomised on an equal basis to also receive either TMC207 (400mg daily for two weeks, followed by 200mg three times a week for six weeks) or a placebo.
Most of the patients (74%) were male, 55% were black and 13% were HIV-positive. Adherence was good with 97% of doses taken in both arms of the study.
An identical proportion of patients in both arms (87%) completed the study. There were no premature discontinuations due to side-effects. The profile of side-effects was similar in the two arms of the study, however the TMC207-treated patients were more likely than those taking the placebo to report nausea (26% vs. 4%, p = 0.04).
The majority of patients achieved the target steady-state plasma concentration of 600 ng/ml throughout the study.
Sputum became smear-negative significantly faster in patients treated with TMC207 in addition to their background therapy than those receiving the placebo. A negative culture was achieved by 48% of patients receiving TMC207 compared to only 9% of those taking the placebo.
Rates of negative smears for acid-fast bacilli at week four of the study were 77% for the TMC207 group and 57% for those receiving the placebo. At week eight this had increased to 84% for the patients taking TMC207 and 68% for patients taking the placebo.
“Our data present evidence that TMC207, in combination with a five-drug second-line regimen, had an acceptable side-effect profile; reduced the time to sputum-culture conversion in patients with newly-diagnosed, smear-positive, multidrug-resistant tuberculosis; and significantly increased the proportion of patients with negative sputum cultures after 8 weeks”, comment the investigators.
The authors of the accompanying editorial believes that both the drug and trial are “very encouraging.” However, he believes that the use of TMC207 is likely to be restricted to second-line TB therapy. This is because the available safety data are limited and “urgently need to be expanded.” Furthermore, the drug is metabolised using the P450 pathway, as is the important anti-TB drug rifampicin, raising the possibility of a negative interaction between the two drugs. Interactions with antiretroviral drugs such as efavirenz and nevirapine, also processed through this pathway, will be investigated by the drug's developer, Tibotec, a Johnson & Johnson company.
Diacon AH et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med 360: 2397-2405, 2009.
Barry CE. Unorthodox approach to the development of a new antituberculosis therapy. N Engl J Med 360: 2466-67, 2009.